HRT safety update

New information is available for this safety alert here.

The HSA Vigilance Branch would like to update healthcare professionals on the recent findings of an 11-year follow-up of post-menopausal women in the Women's Health Initiative (WHI) study and remind healthcare professionals of the importance of appropriate use of hormone replacement therapy (HRT).

Background to the WHI study

The WHI study is a randomised, placebo-controlled trial conducted in postmenopausal women aged 50 to 79 years with an intact uterus. The objective was to assess the major health benefits and risks of the most commonly used combined HRT in the United States – oestrogen plus progestogen therapy (0.625mg conjugated oestrogen plus 2.5mg medroxyprogesterone).¹ The trial, with a planned duration of 8.5 years, ended prematurely in 2002 after a mean of 5.6 years because an increased risk for breast cancer and an overall negative benefit-risk ratio was seen in the HRT group.

In response to the earlier findings from the trial, HSA had published a series of bulletin articles in 2002 and 2004 to update healthcare professionals on the benefits and risks of oral combined HRT in women with an intact uterus.^2,3 HSA requested that product licence holders of the relevant oral combined HRT preparations in Singapore update the study findings in the package inserts of these products. A public advisory was also issued by HSA, in consultation with medical experts in the management of HRT, to advise physicians not to use HRT for the prevention of coronary heart disease.⁴

Latest findings from the WHI study

Following termination of the study intervention phase in 2002, clinical visits and follow-up continued throughout the post-intervention and study extension phases to investigate the long-term effects of combined HRT on cumulative breast cancer incidence and mortality. Continued follow-up for breast cancer incidence was carried out in 12,788 (83%) of the surviving participants from the original trial for a mean of 11 (SD 2.7) years. Results from this continual follow-up of participants showed that oestrogen plus progestogen was associated with a greater incidence of breast cancer compared to placebo (385 cases [0.42% per year] versus 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% CI, 1.07-1.46; p=0.004). In addition, this current analysis found breast cancers in the combined HRT group more likely to be node-positive (81 [23.7%] versus 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; p=0.03).

Breast cancer mortality also appeared to be increased with combined use of oestrogen plus progestogen. There were more deaths directly attributed to breast cancer (25 deaths [0.026% per year] versus 12 deaths [0.013% per year]; HR, 1.96; 95%CI, 1.00-4.04; p=0.049) among women in the combined HRT group compared with women in the placebo group. However, it should be noted that in terms of absolute rates, the risk of breast cancer mortality was low, representing an additional 1.3 deaths from breast cancer per 10,000 women per year attributable to combined HRT. The wide confidence intervals with lower limits close to 1.0 also imply that these results should be interpreted with caution. Similar results were obtained for all-cause mortality after breast cancer diagnosis with 51 deaths (0.053% per year) in the combined HRT group compared to 31 deaths (0.034% per year) in the placebo group (HR, 1.57; 95% CI, 1.01-2.48; p=0.045). Additional secondary analyses conducted to examine the potential effect of excluding data from women who did not re-consent to follow-up supported the primary analyses.

Similar findings from the Million Women Study

The findings from the WHI study were consistent with those from the Million Women Study (MWS), a cohort study investigating the effects of specific types of HRT on incident and fatal breast cancer.⁶ Approximately 1.08 million women aged 50 to 64 years were recruited into the MWS and half of them had used HRT. In the MWS, higher breast cancer mortality was observed in current users of HRT at recruitment compared to those with no prior use (HR 1.22; 95% CI, 1.00-1.48; p=0.05). In current users of each type of HRT, the risk of breast cancer increased with increasing total duration, with an estimated 6 and 19 additional cancers per 1000 users of oestrogen-progestogen combinations after 5 and 10 years of HRT use, respectively.

Local situation

There are eight oral combination oestrogen plus progestogen preparations registered locally. All eight products contain estradiol as the oestrogen component instead of conjugated oestrogens (which was used in the WHI study). These products are contraindicated for use in patients with known, past or suspected breast cancer. To date, HSA has not received reports of breast cancer associated with the use of combined HRT.

HSA's advisory

HSA would like to remind healthcare professionals that HRT does not protect postmenopausal women against cardiovascular events and that HRT should not be initiated or continued for the purpose of reducing cardiovascular risk or preventing coronary heart disease. For the treatment of menopausal symptoms, HRT is beneficial in the short term and should be used at the lowest effective dose, for the shortest duration of treatment. Women on HRT should have their therapy and health reviewed regularly. As the potential harm may outweigh the potential benefits for women who are using HRT solely for the long-term prevention of osteoporosis, it is recommended that patients are made aware of other non-HRT therapies for the treatment and prevention of osteoporosis. Any serious adverse reactions suspected to be related to HRT should be reported to HSA's Vigilance Branch.

References

1. JAMA 2002;288:321-333

2. HSA Adverse Drug Reaction News. August 2002, Vol 4 No. 2

3. HSA Adverse Drug Reaction News. July 2004, Vol 6 No. 2

4. https://www.hsa.gov.sg/announcements/Press-Releases

5. JAMA 2010;304:1684-16

6. Lancet 2003;362:419-427